Fixed prevalence of sulfadoxine-pyrimethamine resistance markers after 3 years of drug pressure
Authors: Nancy Odurowah Duah-Quashie, Kwesi Zandoh Tandoh
Journal: The Lancet Global Health (2023)

In The Lancet Global Health, Antía Figueroa-Romero and colleagues provide scientific-based evidence in support of the continuous usage of sulfadoxine–pyrimethamine for intermittent preventive treatment of malaria in pregnancy (IPTp).1Figueroa-Romero A Bissombolo D Meremikwu M et al.Prevalence of molecular markers of resistance to sulfadoxine–pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation.Lancet Glob Health. 2023; 11: e1765-e1774Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar The authors aimed to determine whether community delivery of IPTp (C-IPTp) has an effect on the selection and spread of drug resistance markers. The study included four sub-Saharan African countries within the Transforming Intermittent Preventive Treatment for Optimal Pregnancy (TIPTOP) project—a multicentre implementation community-based programme designed to increase the uptake of IPTp without compromising antenatal care visits.1Figueroa-Romero A Bissombolo D Meremikwu M et al.Prevalence of molecular markers of resistance to sulfadoxine–pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation.Lancet Glob Health. 2023; 11: e1765-e1774Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 2González R Manun'Ebo MF Meremikwu M et al.The impact of community delivery of intermittent preventive treatment of malaria in pregnancy on its coverage in four sub-Saharan African countries (Democratic Republic of the Congo, Madagascar, Mozambique, and Nigeria): a quasi-experimental multicentre evaluation.Lancet Glob Health. 2023; 11: e566-e574Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar Cross-sectional surveys were conducted at baseline and after 3 years of C-IPTp implementation, and comparisons were made between two groups: an area in which C-IPTp was implemented, and a neighbouring area with no C-IPTp programmes but similar epidemiological characteristics. Children aged younger than 5 years with clinical malaria were recruited from health facilities, and dried blood samples were taken and then used to extract parasite DNA. The dihydrofolate-reductase (dhfr) and dihydropteroate-synthase (dhps) genes of Plasmodium falciparum were sequenced using a MiSeq platform1Figueroa-Romero A Bissombolo D Meremikwu M et al.Prevalence of molecular markers of resistance to sulfadoxine–pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluation.Lancet Glob Health. 2023; 11: e1765-e1774Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 3Ravi RK Walton K Khosroheidari M MiSeq: A next generation sequencing platform for genomic analysis.Methods Mol Biol. 2018; 1706: 223-232Crossref PubMed Scopus (111) Google Scholar to determine the presence or absence of sulfadoxine–pyrimethamine resistance mutations. The authors tested the hypothesis that 3 years of sulfadoxine–pyrimethamine drug pressure would increase prevalence of resistance markers. Figueroa-Romero and colleagues found that sulfadoxine–pyrimethamine resistance markers were either absent in both intervention and non-intervention areas at both timepoints, as was the case for Nigeria and Madagascar, or were present at the same frequencies in both areas over time (Democratic Republic of the Congo and Mozambique). We would have expected an increase in the frequency of sulfadoxine–pyrimethamine resistance genotypes, as suggested by earlier studies.4Mensah BA Aydemir O Myers-Hansen JL et al.Antimalarial drug resistance profiling of Plasmodium falciparum infections in Ghana using molecular inversion probes and next-generation sequencing.Antimicrob Agents Chemother. 2020; 64: e01419-e01423Crossref Scopus (17) Google Scholar, 5Dosoo DK Bailey JA Asante KP et al.The prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine among pregnant women at first antenatal clinic attendance and delivery in the forest-savannah area of Ghana.PLoS One. 2022; 17e0271489Crossref PubMed Scopus (3) Google Scholar, 6Zhao W Li X Yang Q et al.In vitro susceptibility profile of Plasmodium falciparum clinical isolates from Ghana to antimalarial drugs and polymorphisms in resistance markers.Front Cell Infect Microbiol. 2022; 121015957Crossref Scopus (2) Google Scholar As this intuitive expectation was not observed, the authors highlighted several factors that could explain their observations. The evolution of drug resistance in malaria parasites is influenced by multiple factors, including parasite load, multiplicity of infection, parasite genetic mutation rate, the effect of genetic mutations on parasite fitness, duration of drug selection pressure, and an individual's treatment compliance. Furthermore, the authors propose that drug resistance is one of the many factors that determine drug efficacy. Other factors, such as an individual's metabolism of the drug, nutritional status, and naturally acquired immunity, could also play a significant role in drug efficacy. We think another point to be highlighted in the research is the assumption that sulfadoxine–pyrimethamine selection pressure in pregnant women translates into selection of sulfadoxine–pyrimethamine-resistant parasites in children younger than 5 years. For such transmission to occur, the multi-locus genotype characteristic of selected sulfadoxine–pyrimethamine-resistant parasites from pregnant women must not be reversed by the sexual recombination event in the mosquito vector. We propose that the improbability of this scenario helps explain findings. Alternatively, and in the absence of seasonal malaria chemotherapy with sulfadoxine–pyrimethamine, we consider the evolution of sulfadoxine–pyrimethamine-resistant parasites in children younger than 5 years unlikely if sulfadoxine–pyrimethamine therapeutic efficacy is unaffected by IPTp. Therefore, determining the therapeutic efficacy of IPTp in pregnant mothers is important, because using only the prevalence of sulfadoxine–pyrimethamine genotypes of resistance as a proxy for sulfadoxine–pyrimethamine therapeutic inefficacy could be inaccurate. Considering these arguments, we contend that the increasing prevalence of sulfadoxine–pyrimethamine resistance genotypes in sub-Saharan Africa4Mensah BA Aydemir O Myers-Hansen JL et al.Antimalarial drug resistance profiling of Plasmodium falciparum infections in Ghana using molecular inversion probes and next-generation sequencing.Antimicrob Agents Chemother. 2020; 64: e01419-e01423Crossref Scopus (17) Google Scholar, 5Dosoo DK Bailey JA Asante KP et al.The prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine among pregnant women at first antenatal clinic attendance and delivery in the forest-savannah area of Ghana.PLoS One. 2022; 17e0271489Crossref PubMed Scopus (3) Google Scholar, 6Zhao W Li X Yang Q et al.In vitro susceptibility profile of Plasmodium falciparum clinical isolates from Ghana to antimalarial drugs and polymorphisms in resistance markers.Front Cell Infect Microbiol. 2022; 121015957Crossref Scopus (2) Google Scholar juxtaposed with the findings of the authors, presents a prudent reason for conducting therapeutic efficacy studies on IPTp in sub-Saharan Africa. Furthermore, we consider that a corollary to the authors' main finding is the question of whether the research community still needs to discover alternatives to sulfadoxine–pyrimethamine for IPTp. We lean towards the need for novel alternatives. Our reasoning is based on the recognition that evolution of sulfadoxine–pyrimethamine drug resistance is an inevitable event, and that anticipating and planning for chemotherapeutic alternatives is the most prudent course of action for the management of malaria in pregnancy and policy making. In conclusion, we advocate a cautious interpretation and generalisation of the authors' work, especially for policy makers. Despite the authors' finding that there does not appear to be an effect of C-ITPp on sulfadoxine–pyrimethamine resistance mutations, it would be prudent to see how the sulfadoxine–pyrimethamine-resistome landscape evolves with time. We advocate for expanding the number of sub-Saharan Africa countries included in future studies, and using transmission intensities and multiplicity of infection metrics as covariates in determining the evolution of sulfadoxine–pyrimethamine resistant genotypes. We agree with the authors about the importance of their results, which provide another layer of evidence in support of WHO guidelines on IPTp for improving maternal and child disease outcomes.7WHOWHO Guidelines for Malaria, 2022.https://www.who.int/publications/i/item/guidelines-for-malariaDate: March 14, 2023Date accessed: July 25, 2023Google Scholar For now, assuming the authors' findings can be generalised for the entire subregion, we are elated that pregnant women and newborns in sub-Saharan Africa have arguably the best malaria protection evidence can provide. We declare no competing interests. Prevalence of molecular markers of resistance to sulfadoxine–pyrimethamine before and after community delivery of intermittent preventive treatment of malaria in pregnancy in sub-Saharan Africa: a multi-country evaluationC-IPTp did not increase the prevalence of molecular markers associated with sulfadoxine–pyrimethamine resistance after three years of programme implementation. These findings reinforce C-IPTp as a strategy to optimise the control of malaria during pregnancy, and support the WHO guidelines for prevention of malaria in pregnancy. Full-Text PDF Open Access